Human T-cell Leukemia Virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL), an aggressive and fatal disease characterized by a clonal expansion of virus-infected CD4+T cells. It is estimated that 20 to 30 million people worldwide are infected with HTLV-I. ATL has one of the poorest prognoses, with a median survival of 6-9 months in the acute phase and 10-12 months in the lymphoma phase. Overall, survival of ATLL patients treated with various chemotherapy or radiotherapy regimens is limited, as most patients relapse with aggressive tumors and succumb shortly thereafter. The molecular basis of HTLV-I oncogenesis is not well understood. The low incidence and long latency before the onset of the disease suggest that accumulation of genetic alterations of host infected cells is required for disease progression. We have found that microRNA miR-124a is specifically down-regulated through epigenetic silencing of its promoter in ATL cells. In this proposal, we will further characterize the role of miR-124a on the proliferation and survival of HTLV-I infected cells. We will then study the potential cooperation between miR-124a and other microRNA deregulated in HTLV-I transformed cells. Since miR-124a is down regulated in many human cancers, this proposal has the potential for broad implications. PUBLIC HEALTH RELEVANCE: This application proposes to investigate the mechanism by which epigenetic silencing of miR- 124a occurs in HTLV-I infected cells and adult T-cell leukemia (ATL), a fatal lymphoproliferative disease. Since similar changes are also observed in various human cancers, our studies may offer new therapeutic targets for the treatment of human cancers.